Flaxseed and its Cancer Prevention Effects

Flaxseed is the richest known dietary source of mammalian lignans. Thompson et al. demonstrated that secoisolariciresinol diglucoside (SDG), isolated fromflaxseed, was metabolized into both enterodiol
(END) and enterolactone (ENL), and showedchemopreventive properties in the DMBA-induced mammary tumormodel in rats.

The inverse association between a high enterolactone (ENL) concentrationin both urine and serum, and the risk of breast cancer foundin epidemiological studies suggests a chemopreventive actionfor ENL.

Plant lignans, such as secoisolariciresinol (SECO) and matairesinol found in many edibleplants, are transformed by intestinal microbiota into mammalianlignans ENDand ENL, respectively. ENLis the quantitatively most important lignan in human serum.An inverse association between the urinary or serum ENL contentsand the risk of breast cancer has been described in severalepidemiological studies. The finding has stimulatedconsiderable interest in the possible chemopreventive actionof ENL and its precursors.

In pilot human studies, dietary flaxseed given preoperativelyto newly diagnosed breast cancer patients markedly reduced theKi67 labeling index and c-erb2 of the breast cancer tissue,suggesting direct antiproliferative effects. As expected,there was a marked increase in the urinary excretion of mammalianlignans after the ingestion of flax. A recent study of short-termflaxseed supplementation and fat restriction in diet additionallyshowed significantly lower proliferation rates and higher ratesof apoptosis in prostate cancer of men before operation.

However, the observed effects of flax do not allow for any conclusionson the possible role of lignans in the inhibition of cancergrowth, because other potentially bioactive multiple compoundsare present in flaxseed. ENL is assumed to mediate the anticarcinogenic action of plantlignans shown in experimental breast cancer and account forthe antiproliferative effects seen in the clinical studies offlaxseed supplementation. Until recently, there was no direct evidencefor the anticarcinogenic action of ENL in humans or experimentalcancer models in animals. The possible anticarcinogenic effectsof ENL on breast cancer were tested for the first time by usinga DMBA-induced mammary carcinoma of the rat in this study

Hutchins et al. reported increasedserum prolactin concentrations, and decreased serum 17ß-estradioland estrone concentrations in postmenopausal women after a 7-weekadministration of flaxseed in a daily dose of 10 g. It is possible that a long-term exposure to elevated concentrationsof lignans may alter the composition and metabolic activitiesof intestinal microbiota, possibly resulting in altered metabolismof other dietary polyphenols. This study showed elevated serumconcentrations of equol (EQ) and O-desmethylangolensin (O-DMA), metabolites of daidzein (DA), were observed.In premenopausal women, high EQ excretion has been associatedwith lower serum concentration of estrogens and androgens, andhigher concentration of sex hormone-binding globulin, a hormonalpattern consistent with lower risk for breast cancer. Thus,the increased serum concentrations of EQ and O-DMA could accountfor chemopreventive effects observed in this study

ENL and Breast Cancer – The study by Saarinen N et al provided the first evidence that ENL (derived from flaxseed) produced growth inhibition on cancer cells.  In this study rats with 7,12-dimethylbenz(a)anthracene-induced mammary cancers were maintained on a standard open-formula chowdiet. Daily p.o. administration of ENL at a dose of 10 mg/kgof body weight for 7 weeks was shown to significantly inhibited tumor growth.The growth-inhibitory effect of ENL was more pronounced on thenew tumors, which developed during the treatment period, butENL also inhibited the growth of those tumors established beforethe start of the lignan administration. The rat serum concentrationof ENL, which illustrated a permanent positive effect on breastcancer growth, was 0.4 µM, which is >10-fold as comparedwith the serum concentrations found in the general human population.

The effect of ENL was not restricted to any specific histologicaltumor type. ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weightof the 7,12-dimethylbenz(a)anthracene-treated nonovariectomizedrats. (1)

References:

1. Saarinen N, Huovinen R, Warri A, Makela S, Valentin-Blasini L et al. Enterolactone inhibits the growth of 7,12,-dimethylbenz(a) anthracene-induced mammary carcinomas in rat. Molecular Cancer Therapeutics. 2002;1:869-876

Additional Reading On Flaxseed

General Features

Flaxseeds are a rich source of secoisolariciresinol diglycoside (SLD) and other mammalian lignan precursors.  Flaxseed contains 800-times more of these mammalian lignan precursors than is found in any other food (i.e. beans, nuts).   The presence of SLD and related lignan precursors as well as its rich alpha-linolenic acid (omega-3 fat) content makes Flaxseed  a very unique dietary supplement providing a broad range of health-promotion effects.  The consumption of Flaxseed  or processed Flaxseed  (i.e. muffin or bread) has been shown to significantly raise blood levels of the mammalian lignans enterolactone and enterodiol in a dose-dependent manner.  Enterolactone and enterodiol are produced in the colon by the action of bacteria on SLD.^1,4 Both enterolactone and enterodiol act as phytoestrogens and can thus, bind to estrogen receptors on breast (and other reproductive tissues) cells and inhibit certain enzymes (i.e., aromatase enzyme in adipose tissue, also known as estrogen synthase) 2

These, and other synergistic effects have made Flaxseed  a target for breast cancer research.  Other Flaxseed  attributes have stimulated research to examine its potential benefits in the prevention of cardiovascular disease, cancer (i.e. breast, prostate, colon), osteoporosis and the management of menopausal symptoms. 3,4

Principle Active Constituents

• Mammalian Lignan Precursors – In particular: Secoisolariciresinol and matairesinol.  These are converted into the mammalian lignans, enterolactone and enterodiol by colonic bacteria.  Enterolactone and enterodiol are phytoestrogens and exhibit other functions (i.e. antioxidants).

• Alpha-Linolenic Acid (an Omega-3 fat) -The amount of alpha-linolenic acid in Flaxseed Powder is far less than in flaxseed oil (see flaxseed oil, alpha-linolenic acid), which is more likely to provide more significant health-promotion effects related to Omega-3 fat consumption (e.g., anti-inflammatory effects)

• Fiber – Soluble and insoluble fiber ^4,5,6

Clinical Application and Mechanism of Action

• Cancer Prevention and Support

a)  Experimental Evidence- Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions on an experimental basis:

• Compete with estradiol for nuclear binding estrogen binding sites in rat uteri
• Inhibit growth of estrogen-sensitive breast cancer cell lines
• Inhibit angiogenesis of cancer cells
• Inhibit aromatase enzyme, reducing the synthesis of estrone hormone in adipose tissue
• Decrease aberrant crypt and foci in rat colonic epithelium
• Inhibit epithelial cell proliferation in rat mammary gland
• Decrease tumor size in promotion stage of breast cancer in animal studies 5
• Reduced colon cancer development with concurrent intake of Flaxseed  in carcinogen-induced colon cancer experiments with rats 4
• Provide antioxidant protection ⁷
• Lifetime exposure and gestational exposure to Flaxseed  lignans induces cancer prevention structural changes to mammary glands and endocrine changes consistent with a reduced risk of breast cancer development in animals ¹²
• Induce cancer cell differentiation
• Inhibition of tyrosine kinase and DNA topoisomerase – two key enzymes that determine the rate of cell division ⁸
• Anti-mitotic effect ⁴
• Reduction of plasma insulin-like growth factor-1 levels (IGF-1) in rats.  Higher IGF-1 blood levels is associated with an increased risk of breast cancer in some human studies ⁹
• Reduction of pulmonary metastasis of melanoma cells and inhibit the growth of metastasic tumors that formed in the lungs of mice ¹⁰

b)  Human Evidence – Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions in human studies:

• Antiproliferative effect on the breast, similar to that of other selective estrogen receptor modulators, such as tamoxifen and raloxifen ¹¹
• Stimulate production of sex hormone-binding globulin (SHBG), decreasing levels of free unbound sex hormones ¹²
• Decrease the synthesis of 16-alpha hydroxyestrone and increase the synthesis of 2 hydroxyestrone. ¹³  A higher 2 hydroxyestrone to 16-alpha hydroxyestrone ratio (urinary metabolites) has been shown to be related to a decreased risk of breast cancer in women.  This is a suggested “chemoprotective effect”. ¹⁴
• Breast cancer patients excrete very low levels of lignans compared with non breast cancer subjects ⁴
• ^·          Vegetarian women are known to have a lower incidence of breast cancer and exhibit higher blood levels of mammalian lignans ¹⁵
• Improvement in cystic mastalgia, a potentially precancerous condition in women ¹⁶
• Increased or longer luteal phase, increased progesterone to estradiol ratios during the luteal phase, fewer anovulatory cycles, and a decreased tendency to ovarian dysfunction; all of which are linked to a reduced risk of breast cancer in women ⁴

• Cyclical Mastalgia

In a double blind placebo-controlled study by Plu-Bureau et al, they demonstrated that patients ingesting the flaxseed muffin (25gm Flaxseed ) reported a significant improvement in breast pain reduction compared to the placebo group, during the three consecutive menstrual cycle duration of the trial.  Results were attributed to the antiestrogen effects of Flaxseed  lignans. ¹⁶

• Cholesterol Lowering and Other Effects on Reducing Cardiovascular Disease

Animal studies originally suggested that Flaxseed  intake had a hypocholesterolemic effect, that is due to its soluble fiber concentration, not to its alpha-linolenic acid content.¹⁶

In human trials including men and postmenopausal women with high blood cholesterol levels, Flaxseed Powder or Flaxseed  supplementation in various forms has been shown to reduce total cholesterol (approximately 7-10 percent), reduce LDL-cholesterol (approximately 15 percent), reduce lipoprotein (a) (Lp(a)) concentrations by approximately 7 percent.  Lp(a) is emerging as an important risk factor for cardiovascular disease as it increases clotting behaviour of platelets, cholesterol deposition in the artery wall and it oxidizes LDL-cholesterol, making it very atherogenic.

Flaxseed  supplementation is the only dietary factor shown to reduce Lp(a) to date.

Estrogen replacement therapy reduces Lp(a) levels, but cholesterol lowering drugs (i.e. statin drugs) do not ^17,18,19

Flaxseed  lignans inhibit the cholesterol-7-alpha hydroxylase and acyl CoA cholesterol transferase enzymes, involved in cholesterol synthesis, thus reducing total cholesterol. ²⁴

•  Chronic Renal Failure and Renal Disease In Lupus

Animal and human studies indicate that a diet rich in soy based protein and isoflavones, and/or Flaxseed  lignans retard the development and progression of chronic renal disease.  The protective effect is considered to be due to effects on cell growth and proliferation, extracellular matrix synthesis, reduced oxidative stress and inflammation reduction ²⁰

In humans (and animals) Flaxseed  supplementation has demonstrated renoprotective effects in human lupus nephritis, with significant delay in the onset of proteinuria, and preservation of the glomerular filtration rate (GFR) and renal size.

•  Bone Density and Menopausal Symptom Support

Preliminary evidence in women suggests that the phytoestrogen influence of enterolactone and enterodiol (from Flaxseed  supplementation) has a positive effect on bone density and menopausal symptoms (i.e. hot flashes) ¹¹

• Prostate Cancer Protective Effect

Flaxseed  lignans interfere with steroid metabolism and bioavailablity in a fashion that is linked to reduced prostate cancer risk.  They also inhibit enzymes such as tyrosine kinase and topoisomerase, which initiate the cellular proliferation rate.  Epidemiological studies link the above endocrine and molecular events with up to an 80 percent reduction in risk of prostate cancer ²²

• Constipation

Human studies reveal that Flaxseed  supplementation improves laxation ⁵  It appears that Flaxseed  intake increases fecal excretion of bile acids, increasing laxation and reducing the conversion of bile acids to cholesterol in the liver; thereby lowering blood cholesterol ^23,5

DosageRanges

1. General Health and Cholesterol Lowering: 25–50 gms of ground flaxseeds per day (unground seeds are significantly less bioavailable in regards to their lignan precursors content) ^{1, 13,14,17,18,19}
2. Cyclical Mastalgia: 25 gm per day of ground Flaxseed Powder^1,13,14,16
3. Female Menopausal Support: 25-50 gm per day of ground Flaxseed Powder^13,14

Adverse Side Effects and Toxicity

Ground Flaxseed  is extremely non-toxic.  It is well tolerated according to human trails with no significant side effects, other than the occasional report of mild abdominal discomfort ^5,16,23,24

Drug-Nutrient Interactions

There are no well-known drug-nutrient interactions for ground Flaxseed , Flaxseed Powder or Flaxseed -containing products ^1,16,25

References:

1. Nesbitt PD et al. Human metabolism of mammalian lignan precursors in raw and processed flaxseed. Am J Clin Nutr 1995;69(3):549-55
2. Huthcins AM et al. Flaxseed influences urinary lignan excretion in a dose-dependent manner in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9(10):1113-8
3. Tham DM et al. Clinical Review 97 : Potential health benefits of dietary phytoestrogens : a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998;83(7):2223-35
4. Zeigler J. Just the Flax, Ma’am: Researchers Testing Linseed. J Natl Cancer Instit  1994;86(23):1746-8
5. CunnaneSCet al.Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr 1995;61(1):62-8
6. Prasad K et al. Reduction in hypercholesterolemia atherosclerosis by CDC-flaxseed with very low alpha-linolenic acid. Atherosclerosis 1998;136(2):367-75
7. Kitts DD et al. Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol Cell Biochem  1999;202(1-2):91-100
8. Kurzer MS et al. Dietary Phytoestrogens. Annu Rev Nutr 1997;17:353-81
9. Richard SE et al. Plasma insulin-like growth factor-1 levels in rats are reduced by dietary supplementation of flaxseed or lignan secoisolariciresinol diglycoside. Cancer Lett (Ireland) 2000;161(1):47-55
10. Li D et al. Dietary supplementation with secolariciresinol diglycoside (SDG) reduce experimental metastasis of melanoma cells in mice. Cancer Lett 1999;142(1):91-96
11. Brzzinski A, Debi A. Phytoestrogens: the natural selective estrogen receptor modulators? Eur J Obstet Gynecol Reprod Biol 1999;85(1):47-51
12. Tou JC, Thompson LU. Exposure to flaxseed or its lignan component during different developmental stages influences rat mammary gland structures. Carcinogenesis  1999;20(9):1831-5
13. Haggans CJ et al. Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 1999;33(2):188-95
14. Haggns CJ et al. The effect of flaxseed and wheat bran consumption on urinary estrogen metabolism in premenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9(7):719-25
15. Thompson LU et al. Antitumorigenic effect of mammalian lignan precursor from flaxseed. Nutr Cancer 1996;26:159-65
16. Gross PE et al. Effect of dietary flaxseed in women with cyclical mastalgia. Program and abstract of the 23^rd Annual San Antonio Breast Cancer Symposium. Dec 6-9 2000;San AntonioTexas. Abstract 153. Breast Cancer Res Treat. 2000;64:49
17. Arjmandi BH et al. Whole flaxseed consumption lowers serum LDL-cholesterol and lipoprotein (a) concentrations in postmenopausal women. Nutr Res 1998;18:1203-14
18. Jenkins DJA et al. Health aspects of partially defatted flaxseed, including effects on serum lipis, oxidative measures, and ex vivo androgen and progestin activity : a controlled cross over trial. Am J Clin Nutr 1999;69(3):395-402
19. Flaxseed Lowers Cholesterol. Nutr Science News 1998;3(11):575
20. Velasquez M et al. Dietary Phytoestrogens : A possible role in renal disease prtection. Am J Kidney Dis 2001;37(5):1056-68
21. ClarkWF et al. A novel treatment for lupus nephritis : lignan precursor derived from flaxseed. Lupus 2000;9(6):429-36
22. Denis L et al. Diet and its preventive role in prostate disease. Eur Urol 1999;35(5-6):377-87
23. Chen WJL et al. Hypocholesterolemic effects of soluble fibers. In Kritchevsky D, Yahouny GD, eds. Dietary Fiber: basic and clinical aspects.New York: Plenum Press, 1986:275-89
24. Sanghui A et al. Inhibition of rat liver cholesterol 7-alha hydroxylase and acyl CoA : cholesterol acyl transferase activities by enterodiol an enterolactone. In Kritchevsky D, ed. Proceedings of the Symposium on Drugs Affecting Lipid Metabolism.New York: Plenum Press, 1984:311-322
25. Healthnotes Online. Healthnotes Inc. 2000. www.healthnotes.com: Flaxseed